Migraine headache ("migraine") is a common disorder, believed to afflict 20 to 30 percent of the population at large. In migraine patients, throbbing head pain occurs periodically. The pain often is associated with symptoms such as nausea, vomiting and impaired vision. Migraine is a serious clinical disorder requiring medical treatment.
The biochemical mechanisms underlying migraine are uncertain. The predominate belief expressed in the literature for many years was that vasodilation of extracranial vessels causes migraine. Treatment efforts, therefore, were aimed at methods of causing vasoconstriction. More recently, evidence has shown that activation of prejunctional 5-HT.sub.1 heteroreceptors on primary afferent trigeminovascular fibers, by drugs such as ergot alkaloids and sumatriptan, alleviate migraine pain, suggesting a neuronal pathogenesis as opposed to a vascular one. Trigeminovascular fibers innervate meningeal blood vessels. The interaction of these compounds with the 5-HT.sub.1 receptor is very specific. These compounds do not interact with other 5-HT receptors, norepinephrine receptors, glutamate receptors or GABA (gamma-aminobutyric acid) receptors (Moskowitz et. al., Annu. Rev. Med. 44:145-54 (1993)).
Several other studies suggest that a neuronal mechanism is involved in migraine. Clinical studies have reported the usefulness of valproic acid (2-propylpentanoic acid) for the prophylactic treatment of migraine (Herring & Kuritzky 1992, Jensen et al. 1994), chronic daily headache (Mathew & Ali 1991) and for the treatment of cluster headache (Herring & Kuritzky 1989). Valproic acid, commonly used for the treatment of epilepsy, is a GABA transminase inhibitor (Godin et al. 1969) and an activator of glutamic acid decarboxylase (Loscher 1981). Following its administration, GABA levels increase. It was postulated that sodium valproate could be exerting a GABA-mimetic effect by acting on "GABA receptors, including those on the dorsal raphe nuclei, resulting in a decreased firing rate of the seratonergic neurons with a vasodilating effect" and therefore preventing migraine by inhibiting vasodilation. (Jensen, R., et al., Neurology (1994)44:647-651). It however has never been established that sodium valproate mediates its effect via GABA receptors, although the prevailing theory remains that vasodilation is central to migraine.
The above studies as well as others have resulted in the development of several therapeutic approaches for treating migraine; no one mechanism has been identified yet which appears to be responsible for migraine. Drug treatments for migraine include propanolol, methysergide, tricyclic antidepressants, aspirin like-drugs, ergotamine, ergot alkaloids, valproate and sumatriptan. None of the drugs tested thus far have been completely effective or free of side effects. Some side effects result from administering the drug in such high doses that toxicity rises to unacceptable levels. A real need exists to develop a class of drugs which are effective in treating migraine but do not cause significant side effects.
An object of the invention is to provide classes of compounds that are effective for treating migraine.
Another object of the invention is to provide compounds for treating migraine, which have medically acceptable levels of side effects.
Another object of the invention is to identify a biological pathway involved in migraine and to identify drugs that act on this pathway to inhibit, prevent or alleviate migraine.